JPS5835992B2 - Method for purifying natural prostaglandins and synthetic analogs of prostaglandins - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The object of the present invention is a process for the purification of natural prostaglandins and prostaglandin synthetic analogs.

Prostaglandins are known as novel hormones with a broad spectrum of action.

It acts as a vasodilator and bronchodilator in small amounts, it affects fat metabolism and is used as an abortifacient and a labor-inducing agent.

West German Patent Application No. 2155546, 21
59509 and 2117188, prostaglandin esters are known which behave better than the free acids.

The main disadvantage of these esters is that they are mostly oily or poorly crystalline compounds, so that they are difficult to purify and require expensive processes for their production.

After converting brostanic acid into the tertiary amine salt of DE 215 554 using pivaloyl halide, an alkyl- or phenylsulfonyl halide was converted as described in DE 2159 509. initially to form a mixed anhydride, which is then reacted with an alcohol to form a prostaglandin ester.

By the way, it has been discovered that crystalline brostanic acid ester can be obtained in a good yield in one step when brostanic acid is reacted with a certain halogen compound.

The purpose of the present invention is to purify natural prostaglandins and synthetic analogs of prostaglandins, which
Natural prostaglandins or synthetic analogs of prostaglandins can be prepared in the presence of a hydrogen halide scavenging agent with the general formula: ] is reacted with a halogen compound of the general formula: % formula % [where PG represents an acid residue of a natural grosstaglandin or a synthetic analog of prostaglandin, and X represents a direct bond, a carbonyl group or a carbonyloxy Y represents a substituted phenyl ring] and, after purification by crystallization, the ester group is removed by known methods.

Natural prostaglasins refer to all naturally occurring prostaglandins, especially prostaglandins '7A1 and A.
2・El・B2・B3・F1a・F2a・F3a, B1
and B2, analogs of prostaglandin derivatives known from the literature are, for example, 19-oxa-prostaglandin F2a and 13,14-dihydroprostaglandin E1.

Suitable substitutes for the phenyl ring include, in particular, the phenyl group, the alkoxy group having 1 to 2 carbon atoms and the halogen atom, especially the bromine atom in the p-position.

As a hydrogen halide removing agent, for example, silver oxide, Na2
CO3, K2CO3, Na HCo3, KI(CO3
Alternatively, amines, especially tertiary amines such as triethylamine, trimethylamine, tributylamine, trioctylamine and pyridine are used.

The reaction is carried out in an inert solvent, especially acetone, acetonitrile, dimethylacetamide, dimethylformamide or dimethyl sulfoxide, at temperatures between -80 DEG C. and +100 DEG C., especially at room temperature.

By the way, it was surprising that at low equipment costs, the unstable and sensitive brostanoic acid could be converted into the important ester in almost quantitative yields and without decomposition of the starting material. .

The new brostanic acid ester has its excellent crystalline properties.

Its purification therefore poses no difficulties compared to oily starting materials.

Furthermore, it has excellent stability.

Compared to free brostanic acid and conventionally known esters,
It can be stored without problems at room temperature for long periods of time without decomposition.

Brostanic acid ester is an important drug.

This is because, with the same spectrum of action, it has, like the raw acid, a very strong and particularly pronounced long-lasting action.

Some of these compounds show good abortifacient properties in in vivo tests.

@Pregnant Utte was treated with this prostaglandin at 4 to 7 days of Ii pregnancy.

Animals were sacrificed on day 9 and the uterus was examined for implantation location.

In this case, for example prostaglandin F2 (Z and E-
The esters according to the invention of type prostaglandins exhibited an abortive effect at doses 3 to 10 times lower than the corresponding free prostaglandins.

For example, the following novel prostaglandin esters were found to be more effective than natural prostaglandin F2a by an index of n.

To induce miscarriage, 1/n■ of the corresponding new prostaglandin ester is required, and in this case, the amount of prostaglandin F2p required to obtain the same effect is 1■
Met.

Prostaglandin-F2al) 7” rom-phenacyl ester n=3 Prostaglandin-F2ct-p-phenylbenzyl ester
n=10 prostaglandin-F2ct-2.5-dimethoxyphenacyl ester prostaglandin-F2ap-phenylphenacyl ester The ester according to the invention exhibits the typical action of free brostanic acid on the uterine muscles, in particular , PGE-ester showed excellent bronchodilator effect in vitro on isolated rabbit trachea, significantly suppressed gastric juice secretion, and
It has a regulatory effect in the case of visceral periodic movement disorders.

Furthermore, PG-E- and PGA-esters lower blood pressure and act as diuretics.

Another advantage of the present invention is the easy and almost quantitative removal of the ester group.

Therefore, an excellent method for purifying natural prostaglandins and known analogs can be obtained.

This consists in preparing a brostanic acid ester of the general formula I and removing the ester group from this again.

This removal can also be effected advantageously by generally known methods, in particular by reaction with zinc dust in glacial acetic acid [Tetrahedron Lattera 19
1970, p. 343].

Example 1 (Reference example) Prostaglandin E2 (p-biphenylyloxycarbonylmethyl) ester prostaglandin E21001n9, silver oxide 40■,
90 ml of p-phenylphenol bromoacetate is stirred in 2 ml of dimethylacetamide overnight.

Dilute with ether, shake the solution three times with saturated saline solution and evaporate to dryness in vacuo.

The residue is filtered onto a silica gel column with silica gel 302, using a hexane/acetic acid mixture (1:2) for elution.

95 ml of crystalline ester is obtained.

Melting point 80-81°C (from hexane/acetate).

Example 2 (reference example) Prostaglandin F9/YD-phenylbenzi※※
ester prostaglandin F2a 100m9, silver oxide 40m9
．． , 85m9 of p-phenylbenzylfuromide are stirred in 2M dimethylformamide overnight.

Work-up and purification are carried out as described in Example 1.

Yield: 85 ■ ester.

Melting point 83-85°C (from hexane/acetate).

Example 3 Prostaglandin F2Ct P-fromophenacyl ester Prostaglandin F2C1105■, triethylamine 33mg, p-fromphenacilfuromide 9271T
9 was stirred in 4 ml of acetone at room temperature overnight.

It is then diluted with ether, shaken twice with saturated sodium chloride solution, dried and evaporated to dryness in vacuo.

The residue is purified as in Example 1.

Crystalline ester 119mj7 is obtained.

Melting point 95-96°C (from hexane/acetate).

Example 4 Reductive decomposition of phenacyl ester 50 mg of F2aI)-phenyl phenacyl ester and 200 μl of zinc dust are stirred in 4 rrLl of glacial acetic acid at room temperature overnight.

It is then filtered and evaporated to dryness in vacuo. The residue is passed through a silica gel column with silica gel 52.

F2a using chloroform/methanol (4+1)
31rng is obtained.

Analogously to Examples 1-3, the following esters are prepared:

Claims (1)

[Scope of Claims] 1. In order to purify natural prostaglandins and synthetic analogs of prostaglandins, natural grosstaglandins or synthetic analogs of prostaglandins are generally purified in the presence of a hydrogen scavenger. By reacting with a halogen compound of the formula: [wherein Hal represents a halogen atom, particularly bromine, X represents a direct bond, carbonyl group or carbonyloxy group, and Y represents a substituted phenyl ring], crystalline brostanic acid ester is obtained. A process for the purification of synthetic analogues of natural grosstaglandins and prostaglandins, characterized in that after their preparation and purification by crystallization, the ester group is removed by known methods.